Studies on neuroleptic drugs and dopamine (DA) metabolism will be extended. A model for predicting antipsychotic efficacy based on the dose-dependent increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in rat striatum and tuberculum olfactorium has been developed. The study of atypical neuroleptics such as sulpiride, CI-686 and trazodone may reveal whether antipsychotic effects are necessarily linked to changes in DA metabolism and whether these effects are mediated by the striatal or mesolimbic dopaminergic systems. Dose-response and time action curves for these drugs will be generated. The validity of the 3H-haloperidol receptor binding assay for predicting antipsychotic efficacy will be tested using atypical neuroleptics. The relationship between antipsychotic drug concentrations in discrete brain regions and DA metabolism will be studied using gas chromatography to quantitate drug levels. The observation that DA-rich areas selectively accumulate and retain antipsychotic drugs will be explored. The dynamics of DA metabolism will be studied. Studies include the significance of the reuptake process for the formation of DOPAC, the pathways of homovanillic acid formation, and the physiological role of the recently discovered DOPAC-conjugate. Studies on the relationship between gamma-aminobutyric acid (GABA) and DA are planned. L-Glutamate decarboxylase can be potently and specifically inhibited by 2-keto-4-pentenoic acid. This inhibitor and its precursor L-allylglycine will be used to selectively lower GABA levels. GABA-dependent activity will be facilitated by muscimol. The effect of these treatments on DA and its metabolites will be determined.